Download Rate Versus Rhythm Control Pharmacotherapy For Atrial Fibrillation

Rate Versus Rhythm Control Pharmacotherapy
For Atrial Fibrillation: Where are We in 2008?
James A. Reiffel
Department of Medicine, Division of Cardiology, Electrophysiology Section, Columbia University Medical Center, New York, NY.
Abstract
Atrial fibrillation (AF) is the most common sustainedcardiac rhythm disturbance encountered by physicians. The management of AF isfocused on control of heart rate, correction of rhythm disturbance,
andrisk-determined prophylaxis of thromboembolism. The goals of AF therapy are, aswith other serious
disorders, to reduce mortality (if possible) and morbidity(improve quality of life, [QOL]). To this end,
several large studies haveexamined rhythm-control versus rate-control strategies. Although a survivaladvantage to using rhythm control with currently available antiarrhythmic drugshas not been proven, neither has there been a significant excess risk versusrate control. Therefore, using our current therapies, the
results have notsupported rate control or rhythm control as being a preferable first-linetherapy for AF as
regards survival; importantly, neither do they disprove the hypothesis thatmaintenance of sinus rhythm
is preferable to the continuation of AF,particularly if rate control fails to restore adequate QOL. Many
post-hocanalyses and substudies have assessed QOL, functional status, and exercisetolerance, with the
majority demonstrating important benefits associated withachievement of rhythm control. This review
examines rate and rhythm controloptions, the clinical outcomes of several important AF trials, discusses
thelimitations in applying the major morbidity/mortality findings to everydayclinical practice, and summarizes the lessons learned.
Introduction
Atrial fibrillation (AF) is the most commonsustained cardiac rhythm disturbance encountered
in clinical practice.1 It is characterized by the absence of discreteorganized atrial activity on the
electrocardiogram,uncoordinatedatrialactivati
on, disordered contraction of the atrium, and the
deterioration ofatrial mechanical function. AF is
currently estimated to affect between 2.3and 5.1
million people in the United States alone, with expected rates of 5.6to 15.9 million by the year 2050
as an even greater segment of our populationreach older age,2,3 and marked multiples thereof
worldwide. AF’sprevalence has been estimated at 1% in the general population, with higher-
rates in both the elderly (>7% and >10% in women
and men ≥80 yearsold, respectively) and in those
with heart failure (HF) of progressivelyincreasing
severity.2,4 AF often is associated with underlying
structuralheart disease, including hypertension
(~50-80% of AF patients in all recentlarge clinical
trials), coronary artery disease (25%), HF (23%29%), andvalvular heart disease (17%).5
Symptoms of AF may include palpitations,
angina,dyspnea, lightheadedness (and, rarely,
syncope) [all of which may betachycardic related
and/or secondary to the altered mechanics of AF];
chronicfatigue [which, in my experience, almost
always requires restoration of sinusrhythm for
resolution]; and/or impaired exercise tolerance.
Corresponding Address : James A. Reiffel, MD, Professor of Clinical Medicine, ColumbiaUniversity, 161 Fort Washington Avenue, New York, NY 10032.
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However, AF may beasymptomatic at all times in
some patients and at some times in patients withotherwise symptomatic periods or episodes.
Irrespective of symptoms, all-causemortality is
increased 1.5- to 1.9-fold in association with AF
compared withmortality rates in individuals in sinus rhythm.6This may be the consequence of interactions with underlying disorders,consequences
of our therapeutic decisions, consequences of
adversely alteredhemodynamics, and/or consequences of uncontrolled tachycardic rates or emboli.Concordantly with the above, AF can cause
hemodynamic impairment with decreasedcardiac
output; can induce cardiomyopathy and HF, particularly when ventricularrates are rapid; and can
be associated with an increased risk of stroke inselected AF populations.7-9 Health-related qualityof
life (QOL) is adversely affected by the presence
of AF in most patients,with patients potentially
experiencing discomfort due to symptoms, functionalimpairment due to chronic fatigue, exercise
intolerance, and/or the effect oftheir AF-related
medications, and anxiety due to fear of anticoagulationtherapy and the potential for bleeding.10,
11
Furthermore, AFis associated with a significant
economic burden. Healthcare costs areapproximately 5 times higher for patients with AF than
for those without it,and hospitalizations are a key
contributor to this burden.12, 13
Many studies have examined different treatmentoptions (most notably, rhythm versus rate control
strategies) and their successrates in patients with
AF.14-19 Although thestudies conducted to date
with currently available therapies have not demonstrateda survival advantage using rhythm control
strategies versus rate controlstrategies in AF, these
results should not be interpreted to indicate that
rate control is aspreferable a first-line therapy for
AF as is the pursuit of sinus rhythm.Rather, QOL
in AF and its daily impact on the patient must be
considered inaddition to, and, perhaps, at a higher
priority than, the issue of overallsurvival.Commonly, restoration of an acceptable QOL requires
the pursuit ofsinus rhythm, despite the lack of any
simultaneous beneficial survivaladvantage for the
therapy employed. This review examines rate and
rhythmcontrol approaches as well as the clinical
outcomes of several important AFtrials, their limitations, and the lessons learned from them.
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Patterns of AF and their impact on rate andrhythm control considerations
AF presents in specific patterns and can beclassified as paroxysmal (self-terminating) [with some
authors adding thedictate that it last <7 days], persistent (not self-terminating) [with someauthors
adding the dictate that it last >7 days], and permanent (lasting>1 year, being refractory to cardioversion, and/or with sinus rhythm nolonger to be
pursued).20 Paroxysmal AF (PAF) andpersistent
AF are not mutually exclusive as individuals may
experience both atdifferent times. Treatment goals
differ with presentation pattern (Table 1).
AF in patients without evidence of cardiopulmonarydisease, including hypertension, is generally
referred to as lone AF. However,genetic factors
that contribute to the development of lone AF are
beingincreasingly recognized, as are associations
between lone AF and sleepdisorders, autonomic
contributors, and obesity Lone AF is more common
inyounger patients with PAF than in older patients
with persistent AF.21 Although patients with lone
AF have a lower riskof stroke and mortality, their
risk for thromboembolic events andcardiovascular
comorbidities increases with age.22
AF often is a progressive disease, and electrical orpharmacologic conversion of AF to sinus rhythm
becomes less likely and morechallenging when
the arrhythmia has persisted for more than 6-12
months.Between 14% and 24% of patients with
PAF have progression to persistent AF, andpersistent AF not infrequently progresses to permanent
AF.22,23 Both PAF and persistent AF can result in
poor QOL, but thesymptoms that affect QOL often are different for these two AF variants. In therecently reported AFFECTS Registry palpitations,
chest discomfort, anddizziness were found to be
more commonly reported in patients with PAF
whilefatigue and exercise limitations were more
commonly reported in patients withpersistent
AF.24
The rate and rhythm treatment approaches to
PAF areto reduce symptoms during episodes (rate
control) and to reduce the number andduration
of episodes when QOL so demands (rhythm control with a chronicallyapplied regimen). Patients
whose symptoms during and pattern of PAF are-
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acceptable to the patient, especially after rate control has been established,do not require chronic
preventative antiarrhythmic therapy.
The rate and rhythm treatment approaches topersistent AF episodes are to reduce the symptoms during the episodes (ratecontrol) and to
restore sinus rhythm such that permanent AF is
not established(cardioversion, either by pharmacologic or electrical methods), as well as toreduce
the frequency of episodes when QOL so demands
(rhythm control with achronically applied regimen). Infrequent but tolerable persistent AF may
betreated with intermittent cardioversion (which
is especially attractive when itcan be attained
pharmacologically) and does not necessarily require chronic suppressiveantiarrhythmic therapy
(either drug or ablative). This is an important butcommonly overlooked treatment alternative, with
oral class IC single dosetherapy being effective
in up to 80% of patients with a mean conversion
timeapproximating four hours.25, 26
Permanent AF, by definition, requires rate controlbut not the pursuit of rhythm control; however,
recent reports of some successwith restoring sinus
rhythm with ablational approaches even in some
patientswith long-standing ongoing AF may cause
us to revisit our definitions of andour approaches
to therapy of “permanentâ€&AF. Finally, rate
control is needednot only to reduce tachycardic associated symptoms during AF events (seeabove),
but also to prevent the development of a tachycardic inducedventricular myopathy, independent of whether the AF event is itself symptomaticor not.
Rate Control Therapies
Rate control, as has been well described 27 in
many prior reviews, including themost recent
ACC/AHA/ESC guidelines, 20 can beachieved
pharmacologically in most patients using beta
blockers, verapamil ordiltiazem, and digitalis, singly or in combination. Of these, only digitalisdoes
not have the potential to simultaneously reduce
blood pressure. Ingeneral, blood pressure is less
likely to drop with beta blockers than withcalcium channel blockers in older patients. Clinical
pearls concerning ratecontrol are relatively few,
aside from knowing that: 1) clonidine can be used-
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to potentiate the effect of the other above-named
agents, when blood pressureallows, thus enhancing the possibility for adequate rate control but
with thelikewise enhanced risk of sinus nodal and
AV nodal dysfunction if/when sinusrhythm reappears; 2) pindolol is less likely than verapamil,
diltiazem, or anyother available beta blocker to
produce worsened sinus node function inpatients
with the brady-tachy syndrome, and hence, is the
preferred agent inthis condition where its use may
avoid the necessity of inserting a pacemakerto
support the use of an alternative AV nodal blocking agent; 3) ablation of ordrug suppression of an
antegradely conducting bypass tract is necessary
inaddition to AV nodal blockade to attain rate control in patients withpreexcitation; 4) amiodarone
can be effective in providing ventricular ratecontrol but is rarely indicated for this purpose alone
given its toxic profile(whereas, the currently investigational and apparently less toxic derivative
ofamiodarone, dronedarone, may be if and when
it becomes available); [these twoagents can also
provoke sinus nodal and AV nodal dysfunction
in sinus rhythmwhen underlying dysfunction is
present, and, in addition, amiodarone anddronedarone may effect pharmacological cardioversion
beyond rate control, soanticoagulation management is needed if/when these agents are given to
patientswith persistent AF or to patients with PAF
of uncertain or protractedduration]; 5) when drug
therapy is ineffective or not tolerated, ablation of
AVconduction and implantation of a permanent
pacemaker is an appropriate andeffective alternative approach to achieving rate control. Physiologically, thetarget for rate control should be the
attainment of approximately the sameventricular
rate for the same activity state as would be likely
for the patientat hand in sinus rhythm. Thus, since
patients are rarely entirely sedentary,it is not appropriate to judge rate control only by the resting
pulse or theventricular rate on the ECG. Rather,
ambulatory ECG assessment, such as byHolter
monitoring, is the optimal way to determine the
status of rate controlin a patient in AF.20 If only a
resting ECG isperformed, it is not possible to tell
whether residual symptoms during dailyactivity
or exercise are due to inadequate rate control or
whether they persistdespite rate control and will
necessitate the pursuit of sinus rhythm
for their further resolution.
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Rhythm Control Therapies
sive and the debate is often artificial. Ratecontrol is
necessary even when a rhythm control strategy is
being considered. Abolition of symptoms with rate
control may eliminate the necessity forsuppression
of AF, and, rate control will be needed if antiarrhythmic therapyfails to prevent all AF and recurrences occur. Nonetheless, the choice of oneover
the other as the primary strategy is a function of
several factors,including the duration and pattern
of AF, the type and severity of symptoms,the presence of cardiovascular disease, intrinsic AV node
functionality, andthe safety profiles of the treatments under consideration. Of note, prophylaxisof
thromboembolism must be considered irrespective
of treatment strategy; theneed for anticoagulation
therapy is based on the overall risk of stroke –not
on the restoration or maintenance of sinus rhythm,
whether by pharmacologicor ablative approaches.
[However, as anticoagulation is not a focus in thisreview it will not be covered further herein.
Rhythm control requires cardioversion in persistentAF and often requires an antiarrhythmic
strategy (drug or ablation, +/- pacingin bradytachy patients) for the maintenance of sinus
rhythm in both persistentAF and PAF patients. It
is beyond the scope of this review to discuss eitherthe available antiarrhythmic drugs used for
this purpose or the current stateof ablative technology, approaches, and outcomes when used for
AF patients. The interested reader is referred to
the ACC/AHA/ESC management guidelines20
and other recent therapeutic reviews for more detailson specific therapies.
Restoration and Maintenance of Sinus
Rhythm inPatients with AF
The treatment and management of AF are focused
onfour main goals: management of any underlying contributing disorder andreduction of its
pathophysiology when feasible, control of ventricular rate,correction of the rhythm disturbance
when necessary, and prophylaxis ofthromboembolism.20 Although it has often beendebated as
to whether rate or rhythm control is a preferable
strategy, thesestrategies are not mutually excluTable 1
Defining Success in the Treatment of AF
The treatment of AF is ultimately aimed at reducingmorbidity and improving QOL in AF patients,
and, if feasible, reducing any riskof mortality associated with AF in the given patient. However,
AF therapy isnot required for all patients with
AF Patterns and Treatment Approaches(excluding anticoagulation)
PAF
Reduce symptoms during episodes (rate control) and
reduce the number and duration of episodes when
QOL so demands (rhythm control with a chronically
applied regimen)
Persistent AF
Reduce symptoms during episodes (rate control) and
restore sinus rhythm to reduce symptoms and to
avoid permanent AF (cardioversion) as well as to
reduce the frequency of episodes when QOL so
demands (rhythm control with a chronically applied
regimen). Infrequent but tolerable persistent AF may
be treated with intermittent cardioversion (preferably
pharmacologically if possible) and does not
necessarily require chronic suppressive drug or
ablative therapy.
After treatment of a precipitating cause such as acute myocardial infarction , cardiac
or thoracic surgery, hyperthyroidism, pneumonia, or pericarditis
Permanent AF
Reduce symptoms and prevent tachycardia-induced
cardiomyopathy (rate control)
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AF.For example, infrequent, transient,minimally
symptomatic episodes probably do not require
treatment. Moreover,recurrences of this type during drug therapy may not constitute treatmentfailure. Hence, therapy (drug or otherwise) should be
matched to presentation characteristicsand should
be focused on appropriate target goals with a simultaneous concernfor minimizing the potential
for adverse effects. In addition to survival andQOL,
our current state of medical costs and payments
necessitates a thirdtreatment goal: that of reducing
the economic and societal burden of AF.
The determination of whether the pursuit andmaintenance of sinus rhythm should be the primary or default goal for mostpatients with AF has
been the topic of several recent important trials
(Table2).Between 2000 and 2003, five major prospective trials – AFFIRM, RACE,PIAF, HOT CAFE,
and STAF – compared outcomes with rhythm- versusrate-control strategies.14-19 In each of thesetrials
attainment of a significant difference in the primary
endpoint -- amortality benefit or a composite endpoint benefit (or a survival benefit whenassessable
as part of a composite endpoint) -- associated with
rhythm-controlstrategy over a rate control strategy
using intention-to-treat (ITT) analysesproved to be
elusive (see more detailed discussion below). HowTable 2
ever, theseresults should not be taken to suggest
that a rate-control strategy isequivalent to maintenance of sinus rhythm. It merely suggests that,
using anITT assessment of currently available
antiarrhythmic therapies, the rhythm- andratecontrol strategies appear to be equivalent with
regard to length of lifeor composite assessments
including survival. These trials do not disprove
thehypothesis that if one were to attain and maintain sinus rhythm with safermethods than exist at
present, NSR would be preferable to the continuation ofAF. Moreover, and importantly, becauserhythm control did not carry a statistically significant excess risk over ratecontrol in these studies,
the results do not support rate control as asufficient strategy when it does not restore adequate
QOL in patients with AF.
Different study design characteristics andapproaches to analysis can contribute to the challenge in interpreting resultsand pragmatically applying them to patients in clinical practice. Most
clinicaltrials use an ITT approach as their primary
analyses to compare one strategywith another.
For example, in the recent AF trials discussed
herein, allpatients were assigned to a therapeutic strategy, and the outcome was dependenton
the therapy path chosen, not on whether patients
Rate versus Rhythm Control Trials in Atrial Fibrillation
No significant difference in survival or primary
composite endpoint by ITT analysis
AFFIRM 16
RACE 17
STAF18
PIAF 44
HOT-CAFÉ 19
J-RHYTHM 36 Note : Sinus was associated with better event-free survival in PAF subgroup
AF-CHF 37
Improved survival or primary composite endpoints in association with rhythm control (see text)
AFFIRM 30 Subanalysis indicated better survival in sinus rhythm offset by worse survival with antiarrhythmic
drugs
RACE 33,34 Better survival with NSR if it was maintained, but not with antiarrhythmic drugs
DIAMOND Better survival if sinus rhythm was AF 15 attained and maintained
STAF 18 Despite balanced event rates between rate and rhythm control arms, 18 of 19 events occurred during AF; only 1 during sinus rhythm
CHF-STAT 35 Survival was greater in amiodarone-treated patients who attained and maintained NSR than those who remained in AF on amiodarone.
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were in AF or sinus rhythmor whether they actually
received and continued the therapy they wererandomized to receive. Once assigned to a treatment
arm, all patients wereanalyzed as though they were
fully compliant with their therapy and did notcross
over to the alternative treatment, whether or not
this was the case.Outcomes in clinical trials such
as these are further biased by the innateproperties
and adverse effects of the treatments. While the ITT
approach may bestatistically desirable and provide
information on the likelihood of a givenoutcome
if a particular treatment strategy is chosen, it does
not necessarilyprovide information on what actually happens if patients take and continuetherapy.
When discontinuation or compliance rates differ
markedly between twotherapies, this type of analysis is biased. (For instance, a comparison of drugand
nonpharmacologic therapies would inherently be
biased to show greaterefficacy from the nonpharmacologic approach.)
In contrast to ITT analyses, efficacy analyses (also
known as on-therapy or per-protocol analyses) can
be used to evaluate outcomesfor patients who actually initiate and continue without interruption theirassigned therapy. These analyses provide information on the likelihood of aparticular outcome when a
therapy is administered and complied with, but not
onthe likelihood of overall outcomes for therapeutic strategies being compared(i.e., the ITT population). Because some patients may be excluded from
efficacyor on-therapy analyses, such as those never
Table 3
started on therapy, those who donot continue
therapy, etc., unequal group sizes and durations
of therapy (forexample) may arise and confound
the interpretation of findings. The innateproperties and adverse-event profiles of the specific
treatments also maycontribute to bias. For example, patients who discontinue their assignedtreatment early in a study, because of adverse events
or insufficientefficacy create additional bias in
the study results. In the case of AF, oneimportant
contributing factor to the bias in an efficacy analysis is thatcurrently it is usually not realistic to expect that patients will always bemaintained in sinus rhythm in real-world clinical practice (given
the efficacyand adverse event profiles of currently available drugs); thus, a stand-aloneefficacy
analysis without the context of an ITT evaluation
would be of limitedclinical usefulness.
Other important biases may apply to both the ITT
andefficacy/on-therapy analyses; for example, the
definition of treatment successand failure. Historically, a recurrence of AF has been interpreted
as treatmentfailure in AF clinical trials, such as in
time to first event endpoints. Inclinical practice,
such a sole definition of success and failure is notappropriate. A change in the pattern of AF from
"frequent and protracted" to"rare and briefâ"
would constitute clinical success in actual practice. Forexample, in a patient with frequent PAF
if two therapies both reduced episodesto two per
year, whether the first event occurred at 5 months
American College of Cardiology/American Heart Association/European Society for Cardiology Class I Indications for Treating Patients With Atrial Fibrillation With Antithrombotic Therapy
1. Administer aspirin 81 to 325 mg daily for patients with no risk factors
2. Administer aspirin 81 to 325 mg daily or warfarin to maintain an INR between 2.03.0 for patients with 1 moderate-risk factor
3. Administer warfarin to maintain an INR between 2.0-3.0 for patients with any high-risk factor or more than 1 moderaterisk factor.
Moderate-risk factors include age ≥75 years, hypertension, heart failure, LV ejection fraction ≤35%, or diabetes mellitus
High-risk factors include prior stroke, transient ischemic attack or embolism, mitral
stenosis, prosthetic heart value*
*If mechanical valve, the INR should be maintained between 2.5-3.5 Adapted from
Fuster V et al [183]
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or 6 months wouldbe of no real significance clinically. And, perhaps, it may not really matterif
there were two versus three episodes that year.
As with angina, a decreasein the incidence of
AF recurrence should be considered a treatment
success inAF trials. The complete absence of AF
recurrence may be unachievable andimpractical,
whereas fewer and shorter AF episodes would be
a more realisticgoal from the standpoint of everyday clinical practice.
Additionally when assessing a treatment
strategy,the definition of success may confound
clinical and trial impressions. Despitemy discussion of a functionally clear assessment of attainment of adequate ratecontrol above, there have
been substantial differences concerning rate controlassessment in different trials, and various target rates for resting and activestates have been
used. The lack of a well-defined target rate may
lead to lessaggressive titration of rate-control
drugs, which can lead to underestimationof the
adverse-event rates associated with these agents,
and failure to fullyassess the optimum benefits
attainable with these agents. [For example, lowerdoses of beta-blockers are associated with lower rates of adverse eventsbecause many of the
events are dose dependent.] Furthermore, heart
rate mayvary by activity level, time of day, and/
or dosing schedule which can furthercomplicate
interpretation of study results. Similarly, definitions ofeffective therapy endpoints are important
in rhythm control assessments. Forexample, in
patients with infrequent persistent AF or prolonged PAF episodes,termination by intermittent
cardioversion, especially if by oral out-patientsingle dose pharmacologic conversion, may be more
acceptable to the patientthan is the taking of daily
suppressive therapy; yet, in trials such as AFFIRMand RACE, this approach was not a focus of
therapy or of endpoint analysis.
Benefits of Suppressing AF: More than JustProlonging Survival
As with the treatment of any disorder, in AF,
lackof an adverse mortality profile associated
with a therapy is an importantcriterion of success
for any treatment. However, by itself, consideration ofsurvival alone is not a sufficient measure.
QOL in patients with AF has beenshown to be
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46 poorer than that of the general population and
even worse than thatof patients with coronary
heart disease.28 QOLis a subjective measure that
is affected by many consequences of AF, as well
asby its therapy and the patient’s QOL can be
affected on a daily basis by AFsymptoms, complications, and/or therapy. Thus, while a therapy
that reducedsymptoms but increased mortality
would not likely be acceptable, one with noeffect
on QOL with a neutral effect on survival would
also be clinicallyuseless. In addition, as with all
medical decisions, costs associated withtherapies
to be employed must also be considered, and
reduced economic burdenis another important
measure of treatment success. Economic burden
can beinfluenced and measured by hospitalizations, treatment costs, and costs relatedto complications, QOL issues, and the functional status of
patients.
What Benefits Have We Demonstrated for Rhythm
vs RateControl Therapy: A Contemporary Look
at Classical Clinical Trials of AF
Effects on Mortality
AFFIRM
The AFFIRM study (N=4060) compared rhythm
and ratecontrol in patients with AF and a high
risk of stroke or death.16 At 5 years, the ITT analysis showed an overall mortality rate (primaryendpoint) of 23.8% in the rhythm-control group
and 21.3% in the rate-controlgroup (P=0.08).
Interestingly, the ratesof cardiovascular death
(9% and 10%, respectively) and vascular death
(3% and3%, respectively) were comparable between the two treatment arms, whereasnoncardiovascular deaths were significantly higher in
the rhythm-control group(12% vs 8% for rate
control; P=0.0008),29 driven primarily by pulmonary and cancer-relateddeaths. The drug used
most commonly in the rhythm-control arm was
amiodarone(approximately 2/3 of the cases).
Rhythm- and rate-control strategy comparisons
inAFFIRM were limited by the constraints of the
prespecified ITT analysis.16 In AFFIRM, many
patients randomized to therhythm-control arm
remained in AF rather than attaining and maintaining sinusrhythm (17.6%, 26.7%, and 37.4% at
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have been taken to suggest that all patients with
AF with risk markersfor stroke should receive
anticoagulation therapy irrespective of treatment
andrhythm outcome.
1, 3, and 5 years), while many patients inthe ratecontrol arm were in sinus rhythm for some or
most of the time evenwithout an antiarrhythmic
drug (34.6% at 5 years), having suffered only PAF.
Thus, AFFIRM compared treatment algorithms
based on currently availabletherapies and strategies, not outcomes based on whether a patient
was in AF orin sinus rhythm. Two additional observations made in AFFIRM are also importantto
address. In AFFIRM, the use of antiarrhythmic
drugs was associated with a 49% increase in the
risk of death (P=0.0005),with the excess risk being non-cardiovascular deaths, presumed largely
relatedto drug toxicity (see above). Notably, in
AFFIRM, after adjusting for thepresence of sinus
rhythm, sinus rhythm was associated with a better survivalrate (P<0.0001). Importantly,however,
this analysis included patients in the rate control
arm with PAF whowere in sinus rhythm during
follow up visits without the use of anantiarrhythmic agent. The above results suggest that the antiarrhythmic drugsused in AFFIRM were neither
highly efficacious nor safe, at least in thepatient
population enrolled in AFFIRM. Extrapolation of
these results to otherpopulations, such as younger
patients and those without associated riskfactors,
in which therapy options other than those used
in AFFIRM might beconsidered, would/could be
hazardous/inappropriate. Approximately 60% of
theAFFIRM population was male, and most had
persistent AF (69%) rather than PAF(31%). Very
few had lone AF (12%).16 About 23% ofpatients
also had HF. The mean age approximated 70
years. A subanalysis of datafrom AFFIRM suggests that younger patients (<65 years of age) and
those witha history of HF may derive a greater
survival benefit with rhythm-control drugs.31
Additionally one cannot exclude from AFFIRM
thata survival benefit with rhythm control might
occur were the trial to be doneagain with therapies that possesses a better safety profile, should
some becomeavailable. The role of rhythm control in AF patients with HF is being furtherinvestigated in the AF-CHF study (see below).32
Notably,the other factor that was associated with
better outcome in AFFRIM wasanticoagulation.
The incidence of stroke, some of which were fatal, wassomewhat lower in the rate control than
the rhythm control treatment arm.Importantly,
most strokes occurred in patients who had terminatedanticoagulation therapy or were receiving
subtherapeutic levels of warfarin. Thesefindings
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RACE
The RACE trial (N=522) studied patients withpersistent AF and mild to moderate HF who were rate
controlled vs cardiovertedand assigned a rhythm
control therapy.17 Acomposite outcome measure
that included cardiovascular death, hospitalizationsfor HF, thromboembolic complications, severe hemorrhage, pacemakerimplantation, and
severe adverse events was the primary endpoint.
Overall, nodifference in the primary endpoint
was observed between the treatment arms.Moreover, in a subanalysis, patients who remained in
sinus rhythm whilereceiving rhythm control and
anticoagulation did not have a better prognosisfor survival.33 However, a post-hoc analysisshowed that those in sinus rhythm compared with
patients in AF at the end ofthe study had lower
rates of cardiovascular mortality (0% vs 9.5%),
progressionof HF (2.1% vs 4.8%), bleeding (0%
vs 4.8%), and pacemaker implantation (2.1%vs
6.0%) but higher incidence rates of thromboembolic complications (10.6% vs7.1%) and adverse
drug effects (8.5% vs 3.6%).34 These datasuggest
that several clinically important outcomes may
improve when sinusrhythm is achieved and
maintained. The trial was not adequately powered totruly assess mortality risk associated with
treatment approach.
While AFFIRM and RACE taken together suggest
that atpresent, a rhythm control approach has no
survival benefit over a rate controlapproach in
AF, several additional observations may provide
"food for thought" about benefits if sinus rhythm
is attained and maintained.
DIAMOND
The DIAMOND trials assessed the safety of dofetilidevs placebo in heart failure patients. An AF
substudy in DIAMOND, DIAMOND AF(N=506),
investigated the potential of dofetilide to restore
and maintain sinusrhythm in patients with AF or
atrial flutter in this population.15 Differences in favor of dofetilide were observed for the primary
endpoint:cardioversion occurred in 44% of dofet-
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PIAF and HOT-CAFE
ilide-treated patients and 14% ofplacebo-treated
patients over the course of the study (P<0.001).
The 1-year probabilities of maintainingsinus
rhythm were 79% with dofetilide and 42% with
placebo (P<0.001). Importantly, while there was
nosignificant difference in mortality between the
two therapies, regardless oftreatment, the mortality rate was significantly lower in patients whoexperienced restoration and maintenance of sinus rhythm than in those who didnot convert to
sinus rhythm (risk ratio: 0.44; 95%; CI: 0.30-0.64;
P<0.0001).
Two additional small studies comparing rate versusrhythm control, similar in magnitude to STAF,
were also performed at a similarpoint in time:
PIAF and HOT-CAFE.14,19 They, too,revealed no
significant difference in their primary endpoints
by a rate versusrhythm control strategy (using
intention-to-treat analysis), were too small toassess mortality events, and are not detailed further
here. However, relevantinformation on quality of
life derived from these trials is explored below in
asubsequent section of this manuscript.
STAF
CHF-STAT
The STAF pilot trial compared rate vs rhythm
controlin 200 patients with persistent AF.18 There
wasno significant difference between the treatment groups in the primary endpoint,a composite
of death, stroke or transient ischemic attack, systemic embolism,and cardiopulmonary resuscitation, occurring in 9 of 100 patients in therhythmcontrol group and 10 of 100 in the rate-control
group. Notably, however,only 1 of the 19 patients
was in sinus rhythm at the time of the primaryoutcome event (P=0.049), reminiscent ofthe benefit seen in DIAMOND AF if sinus rhythm were
established on dofetilide,and to the AFFIRM substudy regarding the maintenance of sinus rhythm
(seeabove). The above data sets taken in combination do not appear to indicatethat rate control is
as good as rhythm control with respect to survival, butrather, that the benefit of sinus rhythm may
be obscured by the adverse effectsof some of our
rhythm control therapies, at least in some patient
populations. There remains much still to learn.
TThe CHF-STAT trial, which compared ICD
treatment,amiodarone, and best medical therapy
in specific patient types with heartfailure, included
a subgroup of 103 patients who had both AF and
HF atbaseline. Deedwania and colleagues 35 reported theeffects of amiodarone versus placebo in
converting and maintaining sinus rhythmrelative
to survival patterns in this subgroup. Sixteen of
51amiodarone-treated patients (31.4%) and 4 of 52
patients receiving placebo(7.7%) converted to and
remained in sinus rhythm for the duration of the
study(P=0.002). Although no difference inmortality
rate was noted between the two treatment groups
overall, the survivalrate was significantly higher
among amiodarone-treated patients who convertedto and remained in sinus rhythm (n=16) than for
amiodarone-treated patients whoremained in AF
(n=35; P=0.04).The small numbers involved in this
report are too insignificant to weighimportantly in
their own right, but they are consistent with the
sinus rhythmsurvival benefit story built from the
AFFIRM substudy, the trend based uponreduced
mortality (when examined as one component of
the composite endpoint) in RACE, the DIAMOND
AF data, the STAF report, and the J-Rhythm trial
(see below).
PIAF and HOT-CAFE
TTwo additional small studies comparing rate versusrhythm control, similar in magnitude to STAF,
were also performed at a similarpoint in time:
PIAF and HOT-CAFE.14,19 They, too,revealed no
significant difference in their primary endpoints
by a rate versusrhythm control strategy (using
intention-to-treat analysis), were too small toassess mortality events, and are not detailed further
here. However, relevantinformation on quality of
life derived from these trials is explored below in
asubsequent section of this manuscript.
www.jafib.com
J-Rhythm
In the J-Rhythm trial, QOL, a secondary endpoint,
wasassessed using the Atrial Fibrillation Quality of
Life Questionnaire. While thenumber of patients
who completed the questionnaire was not reported
when resultswere presented at the Heart Rhythm
Society meeting in 2007, 36 maintenance of sinus
48
May-June, 2008 | Vol 1| Issue 1
Journal of Atrial Fibrillation
rhythm occurred more frequently in the rhythm
controlgroup than in the rate control group
(P=0.0027)and resulted in greater improvements
in the frequency and duration of symptomsamong patients with PAF. The severity of symptoms and AF-related anxiety andlimitations of
activity were similar in the two therapeutic arms.
Maintenance of Sinus Rhythm and Progression of AF
Although results from the studies reviewed hereinsuggest, but do not yet prove, that there are
benefits to achieving sinusrhythm with respect
to overall mortality, and almost uniformly suggest thatsinus rhythm is associated with a better
QOL than is AF inmost patients, it ismore difficult to assess the important issue as to the role
of sinus rhythmcontrol in preventing the progression of AF from the initial episode topermanent AF. Dittrich and colleagues 48 showedthat
maintenance of sinus rhythm at 1 month after
cardioversion was more likelyin patients with
an AF duration of <3 months than in those with
AF durationof >12 months (P<0.05). This isconsistent with the hypothesis that there is greater
potential for reverse remodelingand long-term
maintenance of normal sinus rhythm when
normalization is achievedearly in the course of
treatment. In addition, the PAF 2 trial showed
thatpharmacologically controlled sinus rhythm
after ablation and pacing therapylowered the
risk of progression from PAF to permanent AF
by 57% (P=0.02).49 Similarly,RACE demonstrated that maintenance of sinus rhythm was associated with reducedatrial size (remodeling) and
improved left ventricular function (P<0.05)50
and in HOTCAFE, only patients in the rhythmcontrol group had an increase in leftventricular
fractional shortening (P<0.001).19
Just as the results of these studies are consistentwith a progressive model of AF pathophysiology and suggest a possible role forearly
intervention to reverse and/or prevent the progression of AF, so too arethe observations in several drug and ablation studies which have shown
thatatrial size can regress toward normal and
atrial function can improve with theattainment
of sinus rhythm. However, complete normalization of size and fullrestoration of function do not
www.jafib.com
Featured Review
generally occur and further investigation intothese
remodeling issues is required, and, in addition, little
data existregarding restoration of atrial secretory
function and reduction in biochemicalthrombogenic factors in patients who achieve and maintain
normal sinus rhythm.Thus, discontinuation of anticoagulation should not be considered at this timefor
AF patients with a significant CHADS2 score despite theirconversion to and maintenance of sinus
rhythm.
One additional observation
There are several additional important AF trialsbeyond those cited above. They have not been explored
herein as they did notcompare rate versus rhythm
control strategies, did not assess mortality as atarget
(alone or part of a composite) in their primary endpoint, and/or did notprovide additional important
analyses re quality of life outcomes. However,two,
the RAFT and ERAFT trials, pivotal to the approval
of sustained releasepropafenone for the maintenance of sinus rhythm in AF patients,51,52 are worth
mention for one additional purpose. RAFTwas a
prospective, double-blind, placebo-controlled trial
designed to test theefficacy and safety of 225 mg,
325 mg, and 425 mg bid in reducing the frequencyof
symptomatic recurrences in patients who were in
sinus rhythm but had ahistory of symptomatic AF.
ERAFT was a prospective, double-blind,placebocontrolled trial designed to test the efficacy and
safety of 325 and425 mg bid (but not 225 mg) efficacy in reducing recurrent symptomaticparoxysmal AF in patients with prior symptomatic AF who
were in sinus rhythm atdrug initiation. Both trials
documented a superior efficacy for sustainedrelease
propafenone over placebo (and contributed to FDA
approval of theproduct) but the relative efficacy
rates of identical doses were different inthe two trials. In RAFT, the median time to the occurrence of
a primaryoutcome event was 41 days for placebo,
291 days for 325 mg bid, and >300days for 425 mg
bid (the latter being a non-exact number because a
largepercentage of patients did not have any recurrence on the 425 mg bid dose). InERAFT, the median
time to occurrence of a primary outcome event was
9 days forplacebo, 35 days for 325 mg bid, and 44
days for 425 mg bid. Why is there sucha discrepancy
in the time to first recurrence with the same drug
and dose inthe two trials and what lesson is there to
learn from this? The major reasonis the difference in
49
May-June, 2008 | Vol 1| Issue 1
Journal of Atrial Fibrillation
Featured Review
the patient demographics, with the ERAFT patients
having amuch longer AF history and more frequent
prior events than the patients inRAFT. The lesson
to be learned is that one cannot safely or effectivelycompare the magnitude results of drug outcomes
across different trials, evenwhen using the same
agent in the same dose(s). Only direct comparisons
in asingle trial with a single population can be considered accurate. Furthermore,because beta blockers and, to some extent, verapamil, through sympatholyticactions, can enhance the electrophysiologic
and antiarrhythmic effects ofantiarrhythmic drugs
(such as by preventing their reversal during times
ofspontaneous increased sympathetic activity, e.g.,
stress, exercise),differences in concomitant rate control drugs across different clinical trialsmay also
confound accurate assessment of magnitude of antiarrhythmic drugeffects in different trials, and even,
at times, within a single trial. Nonetheless, directional similarities across trials do provide importantobservations.
Conclusions: Lessons Learned
The clinical trials conducted to date in patientswith
AF do not show an advantage to a strategy of
rhythm control over ratecontrol. However, based on
the available data, clear and thorough comparisonsof outcomes between patients who achieve normal
sinus rhythm and those whoachieve rate control
are not possible because of the variety of limitationsdiscussed above. For example, use of the ITT approach to data analysis is notparticularly relevant to
everyday practice, but is the primary method –and
sometimes the only method – of analysis reported
in peer-reviewedpublications. Also problematic is
the fact that many patients will remain in AFdespite
treatment with the currently available antiarrhythmic drugs, and thislack of efficacy is frequently accompanied by adverse-event profiles that areless
than ideal. In contrast, it is important to note that
several non-ITTanalyses have found reductions in
mortality and improvements in QOL, functionalstatus, and exercise tolerance when sinus rhythm
was achieved and maintained.From a theoretical
standpoint, early restoration and maintenance of
sinusrhythm also may result in reversal of atrial remodeling and in slowing or preventingAF disease
progression, and this merits some consideration.
Therefore, whenconsidering the currently available options for treatment, it should beremembered
www.jafib.com
50
that no single strategy is universally beneficial,
and treatmentmust be individualized for each
patient. The development of new antiarrhythmicdrugs with improved efficacy and tolerability profiles and additional dataconcerning
the absolute and comparable value of ablative
approaches shouldfacilitate a more meaningful
and detailed assessment of the benefits of sinusrhythm control strategies in patients with AF.
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